title: The K(+) channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia.
abstract: The use of opioid agonists acting outside the central nervous system (CNS) is a promising therapeutic strategy for pain control that avoids deleterious central side effects such as apnea and addiction. In human clinical trials and rat models of inflammatory pain, peripherally restricted opioids have repeatedly shown powerful analgesic effects; in some mouse models however, their actions remain unclear. Here, we investigated opioid receptor coupling to K(+) channels as a mechanism to explain such discrepancies. We found that GIRK channels, major effectors for opioid signalling in the CNS, are absent from mouse peripheral sensory neurons but present in human and rat. In vivo transgenic expression of GIRK channels in mouse nociceptors established peripheral opioid signalling and local analgesia. We further identified a regulatory element in the rat GIRK2 gene that accounts for differential expression in rodents. Thus, GIRK channels are indispensable for peripheral opioid analgesia, and their absence in mice has profound consequences for GPCR signalling in peripheral sensory neurons.
authors.affiliation: Klinik für Anaesthesiologie und Operative Intensivmedizin, Freie Universität Berlin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, Germany.
authors.forename: Dinah
authors.initials: D
authors.lastname: Nockemann
authors.forename: Morgane
authors.initials: M
authors.lastname: Rouault
authors.forename: Dominika
authors.initials: D
authors.lastname: Labuz
authors.forename: Philip
authors.initials: P
authors.lastname: Hublitz
authors.forename: Kate
authors.initials: K
authors.lastname: McKnelly
authors.forename: Fernanda C
authors.initials: FC
authors.lastname: Reis
authors.forename: Christoph
authors.initials: C
authors.lastname: Stein
authors.forename: Paul A
authors.initials: PA
authors.lastname: Heppenstall
mesh_terms: D000368:Aged; D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D006801:Humans; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D017933:Peripheral Nervous System / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human; C497069:Kcnj6 protein, mouse; C497070:Kcnj6 protein, rat; D015221:Potassium Channels; D011957:Receptors, Opioid
keywords: Dorsal root ganglia; Ion channel; Opioids; Pain; Peripheral analgesia